Skin-Related Complications of Insulin Therapy

Am J Clin Dermatol 2003; 4 (10): 661-667LEADING ARTICLE 1175-0561/03/0010-0661/$30.00/0

© Adis Data Information BV 2003. All rights reserved.

Skin-Related Complications of Insulin TherapyEpidemiology and Emerging Management Strategies

Tristan Richardson and David Kerr

Bournemouth Diabetes and Endocrine Centre, Royal Bournemouth Hospital, Bournemouth, UK

The incidence and prevalence of all types of diabetes mellitus is increasing at an alarming rate. ModernAbstracttherapy involves greater and earlier use of intensive insulin regimens in order to achieve better control of bloodglucose levels and reduce the long-term risks associated with the condition. Insulin therapy is associated withimportant cutaneous adverse effects, which can affect insulin absorption kinetics causing glycemic excursionsabove and below target levels for blood glucose.

Common complications of subcutaneous insulin injection include lipoatrophy and lipohypertrophy. Thedevelopment of lipoatrophy may have an immunological basis, predisposed by lipolytic components of certaininsulins. Repeated use of the same injection site increases the risk of lipoatrophy – with time, patients learn thatthese areas are relatively pain free and continue to use them. However, the absorption of insulin fromlipoatrophic areas is erratic leading to frequent difficulties in achieving ideal blood glucose control. With theincreasing use of modified, rapidly absorbed analog insulins (e.g. insulin lispro, insulin aspart) the incidence oflipoatrophy occurring has decreased over recent years. The likelihood of lipoatrophy can be reduced by regularrotation of injection sites but once developed, practical benefits may be obtained by insulin injection into theedge of the area, co-administration of dexamethasone with insulin, or changing the mode of insulin delivery.

Lipohypertrophy is the most common cutaneous complication of insulin therapy. Newer insulins have alsoreduced its prevalence considerably, although its adverse effect on diabetic control is similar to lipoatrophythrough impaired absorption of insulin into the systemic circulation. Experience with liposuction at these sites islimited, although good cosmetic results have been achieved.

Local allergic reactions to insulin are usually erythema, pruritus, and induration. These allergic reactions areusually short-lived, and resolve spontaneously within a few weeks. Useful adjuncts to managing allergicreactions include addition of dexamethasone to the insulin injection, desensitization to insulin, or a change indelivery system utilizing insulin pump therapy or potentially inhaled insulins when these become available. Theuse of insulin pump therapy in managing cutaneous complications of insulin therapy is increasing, but thismethod itself carries risks of abscess formation and scarring. Fortunately, with improved education of patientsthese are relatively uncommon.

Although many of the cutaneous manifestations are decreasing with the use of newer insulins, they may stillinfluence glycemic control and increase the risk of hypoglycemia as well as have a cosmetic impact on a patient.The introduction of novel therapies and newer delivery systems is likely to reduce the cutaneous problemsassociated with long-term insulin use.

The number of people with insulin-treated diabetes mellitus has and reduce their risk of developing long-term complications asso-risen exponentially over recent decades for two reasons. Firstly, ciated with the condition – retinopathy, nephropathy, and neuro-there has been a marked increase in the incidence of type 1 pathy. There has also been a significant rise in the prevalence ofdiabetes, trebling in some parts of the UK over the last 30 years.[1] type 2 diabetes (see figure 1) particularly among ethnic communi-Secondly, more people with type 2 diabetes are being treated with ties.[2] In part this reflects the growth in the number of peopleinsulin in order to achieve improved standards of glycemic control becoming overweight or clinically obese.

662 Richardson & Kerr

1990 1995

2000

No dataLess than 4%4–6%Above 6%

Fig. 1. Type 2 diabetes mellitus and gestational diabetes trends among adults in the US, 1990 (reproduced from Mokdad et al.[2] Copyright© 2000American Diabetes Association. From Diabetes Care, Vol. 23, 2000; 1278–83. Reprinted with permission from The American Diabetes Association),1995[3] and 2000[4]

Diabetes is associated with a number of dermatological compli- insulin. These may, in themselves, cause problems related tocations, some related to the disorder itself, but a proportion are a glycemic control and recurrent hypoglycemia as a result of alteredconsequence of drug therapies used in its treatment (table I). insulin absorption and pharmacokinetics, as well as cosmeticAlthough the most common adverse effects of insulin therapy are difficulties.hypoglycemia and weight gain, there are a number of skin-related

1. Complications of Insulin Therapycomplications associated with regular subcutaneous injections of

1.1 Lipoatrophy

Insulin-induced lipoatrophy is the loss of subcutaneous fat atthe site of injection (see figure 2). Typically, presentation occursafter 6–24 months of regular insulin treatment, and is more com-mon in young people and in those who have had previous dermalreactions to insulin. Prior to the introduction of purified humaninsulin, lipoatrophy occurred in 25–55% of patients, however,with the introduction of highly purified insulins, <10% of patientsare now affected.[5,6] Incidence rates are likely to have fallenfurther with increased use of recombinant analog insulin althoughthere have been case reports of lipoatrophy in patients regularlyusing the newer preparations.[7,8]

The pathological mechanisms related to development of lipoa-trophy are unknown but may involve lipolytic components ofcertain insulin preparations or an immune-mediated inflammatory

Table I. Skin complications related to diabetes mellitus and its treatment

Diabetes mellitusa Sulphonylureasa Insulin

Necrobiosis Maculopapular rash Lipohypertrophylipoidicadiabeticorum

Diabetic Photoallergic reactions Lipoatrophydermopathy

Diabetic thick skin Phototoxic reactions Abscess

Diabetic bullae Lichenoid/rosacea-like Insulin edemaeruptions

Acanthosis Stevens-Johnson Idiosyncratic skinnigricans syndrome reactions

Yellow skin Erythema nodosum Insulin Allergy

Pigmented purpuric Chlorpropamide flush Zinc/protamine allergydermatoses

a Discussion is beyond the scope of this article.

© Adis Data Information BV 2003. All rights reserved. Am J Clin Dermatol 2003; 4 (10)

Skin-Related Complications of Insulin Therapy 663

process with the release of lysosomal enzymes promoting lipoa-trophy.[10] In support of an immune process, high levels of circulat-ing anti-insulin antibodies with deposition of Immunoglobulin(Ig)M, complement component 3 (C3), or fibrin-fibrinogen in theedge of the lipoatrophic site have been demonstrated in thesepatients.[11,12]

Once lipoatrophy develops, general advice is that patientsshould avoid injection into these areas. Unfortunately, spontan-eous resolution is rare. Repeated injections of highly purifiedporcine or human insulin into the affected area have been asso-ciated with >90% regression of the atrophic areas and re-accumu-lation of fat cells.[13] Once regression occurs, occasional insulin

Fig. 3. Lipohypertrophy.injection may be needed to maintain a relatively normal appear-ance. Changing to highly purified or recombinant (analog) insulin

age, low body mass index, use of the abdomen for injection, andand injecting into the edge of the atrophic area may also improvenot rotating injection sites on a regular basis.[17]

appearance.[14]

Lipohypertrophy usually presents as soft dermal nodules withinIf these measures fail and reaccumulation of fat does not occur,the normal surface epidermis with fat cell hypertrophy – a conse-the addition of dexamethasone (4 μg/unit) to the insulin injectionquence of the lipogenic effect of insulin. Unfortunately, patientsmay be effective in restoring fat deposition.[15]

often continue to inject at these sites preferentially due to theirOther management strategies include switching to continuousrelative anesthesia. The lipohypertrophic nodules have decreasedinsulin infusion (insulin pump) therapy [16] or, in the future,vascularity, which invariably impairs insulin absorption (see fig-switching to alternative modes of insulin delivery such as the useure 3).[18,19]

of inhaled insulin (see section 2).Once lipohypertrophy develops, the treatment is to rotate injec-

tion sites in the hope that regression will occur. Changing to the1.2 Lipohypertrophy short-acting, rapidly-absorbed analog insulins may be a useful

adjunct to site rotation.[20] As with lipoatrophy, novel approacheshave included switching to pump therapy where the overall insulinLipohypertrophy was, and still is, the most commonly reportedrequirements are reduced, lessening the lipogenic stimulus. Pumpcutaneous complication of insulin therapy. Since the introductiontherapy requires a change of infusion site every 2–3 days asof highly purified human insulins, the prevalence of lipohyper-opposed to four injections each day for individuals using standardtrophy has dropped to <30% in patients with type 1 diabetes andmultiple injection therapy.<5% in patients with type 2 diabetes.[17] The development of

lipohypertrophy is associated with recent insulin initiation, young If avoidance of affected areas or any of the other therapeuticoptions fail, removal of the affected site may be desirable. Li-pohypertrophy can be treated successfully with syringe-assistedliposuction under local anesthesia. Good cosmetic results havebeen achieved in one small study[21] with minimal adverse effectsor complications resulting from the procedure. Patients appearedto be pleased with the final cosmetic appearance of the sites withonly small surface irregularities seen in those who had largevolumes of fat removed from the proximal anterior thighs. To date,there is limited experience with liposuction in the treatment ofinsulin-induced lipohypertrophy.

1.3 Allergy

Twenty years ago allergic reactions to insulin were said tooccur in approximately 50% of patients.[22] These reactions are

Fig. 2. Lipoatrophy (reproduced from Griffin et al.[9] Copyright© 2001 Amer-ican Diabetes Association. From Diabetes Care, Vol. 24, 2001; 174. Re-printed with permission from The American Diabetes Association)



less common today, but the majority of patients still have some differs by just one amino acid. This is supported by the reductionin incidence of allergy seen since the introduction of humanimmunological reaction to insulin. The development of low titersinsulin.[22]of insulin binding antibodies is frequent,[23] but very few individu-

als treated with purified human insulins (<3%), develop local There is little supporting evidence for non-insulin protein con-reactions,[22] and only 0.01% experience systemic allergic reac- taminants as a cause of allergic reactions. Prior to 1972, insulintions.[24] contained 1000 parts per million (ppm) of impurities. Since then,

human insulin has been refined to contain <10 ppm.[23] This hasLocal reactions to subcutaneous insulin tend to be erythema-lead to a reduction in allergy, and may suggest that the allergentous, pruritic, occasionally indurated and occur at the site of thepromoters are contaminants within the insulin injection. However,injection (see figure 4). Isolated wheal-and-flare reactions, medi-in a group of insulin allergic patients, pro-insulin, the most com-ated by IgE antibodies to insulin with mast cell activation, can alsomon non-insulin protein contaminant, was shown to have nooccur. Symptoms usually resolve after one hour. These monophas-intradermal reactivity[28] suggesting that pro-insulin was not toic responses typically occur one week after initiation of therapy.blame as the causative allergen.More commonly, IgG-mediated effects are biphasic, with an initial

Zinc and protamine contained in neutral regular insulin andwheal-and-flare reaction, followed by a late-phase peaking at 4–6neutral protamine Hagedorn (NPH) have been associated withhours and lasting for ≤24 hours. Induration at the injection sitecutaneous allergic reactions.[29,30] In one study, 11 patients withmay last longer, occasionally several days. Delayed tuberculin-cutaneous allergy to insulin underwent intradermal skin testing. Oflike reactions can also develop. These are cell-mediated develop-these, five had positive reactions to protamine sulphate and fouring 8–12 hours post-insulin administration, peaking at 24 hours,were positive to insulin.[30] It is noteworthy that 15% of the controland lasting for several days. Such reactions are well defined,group also experienced localized skin reactions when exposed topainful, itchy, and characterized by a local mononuclear infil-high concentrations of protamine sulphate. In vitro assays havetrate.[11]

demonstrated elevated levels of IgE and IgG to protamine amongSystemic allergy with urticaria, generalized rash, pruritus, or

patients using NPH insulin, but not in patients using regularparesthesia is very rare. Angioneurotic edema and circulatory

human insulin, suggesting that anaphylactic reactions to NPH arecollapse have also been described in association with insulin

related to the protamine component.[31] Desensitization to insulinuse.[25] Treatment is similar to anaphylaxis of any cause.[26]

and protamine has been successful in patients with insulin allergyThere has been controversy over which component of the in whom standard insulin desensitization did not completely re-

injection is causative in initiating an allergic reaction; for example, solve allergic symptoms.[32]

the insulin molecule itself, pro-insulin in unpurified insulin prepa- Allergic reactions to insulin zinc suspension have also beenrations, or zinc or protamine contained in the longer-acting formu- described using intradermal skin testing. Changing to zinc-freelations. The difference in the amino acid sequences in bovine, insulin can result in amelioration of cutaneous allergy.[29] How-porcine and human insulin has been cited as a reason for the ever, in others changing to zinc-free insulin is not associated with agreater antigenicity of bovine insulin versus porcine and human reduction in symptoms.[33]

insulin.[27] Bovine insulin differs by three amino acids in the The rise in the use of analog insulins has resulted in a reductionprimary sequence from human insulin whereas porcine insulin in the use of both human and NPH insulin, resulting in a reduction

of allergic reactions although case reports of allergy continue toappear.[34]

Local skin reactions are usually short-lived, and resolve sponta-neously within a few weeks despite continuation of insulin. Anti-histamines are useful in symptom control and can block the wheal-and-flare response. If the skin reactions persist longer than 2–4weeks, then changing insulin to the less allogenic types, e.g. thenewer analog insulins, may be beneficial.[35] If changing insulindoes not resolve the allergic reaction, there are a number ofpotential options to be considered including:

• dividing the dose and varying the delivery site

• the addition of 1μg of dexamethasone to each unit of insulin perinjectionFig. 4. Local reaction to insulin injection.



• oral antihistamines (or corticosteroids)

• inhaled insulin when this becomes available

• continuous insulin infusion (pump) therapy

• insulin desensitization.A number of desensitization schedules have been pro-

posed,[14,36] some of which have achieved good success rates.Rarely desensitization is not successful in patients with poorglycemic control, and infrequently desensitization may be asso-ciated with an augmentation of insulin resistance.[37] Novel ap-proaches to insulin allergy, for patients who are unresponsive toinitial methods, are the use of inhaled insulin (described in section2) or changing to continuous insulin infusion therapy.[38,39]

Fig. 5. Abscess associated with insulin pump therapy.1.3.1 Insulin Pump Therapy

The Diabetes Control and Complications Trial (DCCT)[40] con- mation do occur.[44] Most cases are bacterial, usually Staphylococ-firmed that tight control of blood glucose is associated with a cus spp. or Streptococcus spp., although infection withreduction in microvascular complications associated with type 1 Rhizomucor spp. has been reported.[45]

diabetes. In the intensively treated arm of the DCCT, 42% of In a 4.5-year follow-up study of 116 type 1 diabetic patients onpatients were using insulin pumps. Since publication of the DCCT, long-term insulin pump therapy there were 134 episodes of subcu-pump usage has risen exponentially. There are currently >120 000 taneous inflammation (0.26 cases of inflammation per patient-people with diabetes using continuous subcutaneous insulin infu- year).[46] Thirty five patients required antibacterial treatment and/sion (CSII) in the US. or surgery. At follow-up examination, 48% had white scars over

Modern insulin pumps are about the size of a pager, which can the abdomen (the most common site for pump insertion) as abe attached to clothing or can fit in a pocket. The pump infuses consequence of previous skin infections, while 51% of patientsinsulin via a fine bore tube and rubber cannula placed in the had erythema concurrent with pump use. Subcutaneous nodulessubcutaneous fat of the abdomen, thigh, or arm. were palpable in 19% and inflammation requiring antibacterial

The advantages of insulin pump therapy relate to more predict- treatment was found in 1.7% of patients. The relatively highable insulin pharmacokinetics and a reduction in insulin dosage. incidence of cutaneous complications in this study was thought toThese include: be associated with poor hygiene.[47]

• reduced intra-regional variability of glucose absorption as CSII In another study in patients with type 1 diabetes using insulinuses a single injection site for 2–3 days pump, 58 of 120 pump needles were found to be contaminated, the

• reduced insulin dosage and major hypoglycemic events majority colonized with Staphylococcus epidermis. This was asso-

• enhanced patient freedom in relation to timing of meals and ciated with cutaneous inflammation around the insertion site. Withsnacks.[41] the introduction of topical disinfectants, serious infections haveThere are a number of dermatological indications for insulin declined substantially suggesting that these complications can be

pumps, including treatment of insulin allergy and lipohypertrophy. successfully be prevented by appropriate antiseptic measures.[47]

The most common complication associated with use of an insulin1.5 Idiosyncratic Skin Reactionspump is infection at the infusion site; this is associated with

chronic carriage of Staphylococcus aureus.[42]

The most common reaction is simple bruising which most oftencauses cosmetic problems. Pigmentation can occur at injection1.4 Skin Abscessessites, sometimes leading to plaque formation resembling

Skin abscesses due to insulin injection per se are vanishingly acanthosis nigricans.[48] Rarely keloids can develop. Localizedrare. However, skin abscess or cellulitis because of continuous amyloidosis has also been described in relation to insulin therapy,insulin infusion is one of the most common causes listed for and can be mistaken for lipohypertrophy.[49] Amyloid infiltrationdiscontinuation of pump therapy (see figure 5).[43] can occur at the site of injection, and insulin per se has been

Infusion sets need be changed every 2–3 days. In most cases, associated as one of the many proteins that can form amyloidsimple washing of the skin is all that is necessary before inserting fibrils.[50] Amyloid lesions are more firm and solid than those ofinfusion sets. Nevertheless, skin infections, including abscess for- lipohypertrophy, and are unlikely to regress after injection site



rotation. As with lipohypertrophy, insulin absorption may be 3. Conclusioninfluenced and treatment by excision may be appropriate. Diag-

Skin complications related to insulin therapy are common,nosis at excision or biopsy is by usual histological methods andunsightly, distressing to the patient, and potentially have importantstaining.effects on metabolic control. Until recently, therapeutic options totreat these complications have been limited and often unsuccess-

1.6 Insulin Edema ful. With the use of new analog insulins, skin-related adverseeffects of insulin therapy are less common but remain trouble-

Peripheral edema related to insulin therapy is rare but well some. Alternative routes of insulin administration are being devel-recognized. It is most often associated with insulin initialization or oped but long-term data on efficacy and safety are required beforea large change in insulin dosage. Weight gain over a short period their use becomes widespread.of time is the most common feature, although severe reactionshave progressed to congestive cardiac failure and/or ascites. In- Acknowledgmentscreased transcapillary leakage has been demonstrated in some

No sources of funding were used to assist in the preparation of thiscases following the use of excessive insulin.[51]manuscript. The authors have no conflicts of interest that are directly relevantto the content of this manuscript. We would like to thank the Royal Bourne-Treatment consists of a reduction in insulin dose. Usuallymouth Hospital Department of Medical Photography for their help in prepar-edema is self-limiting and diuretic therapy is not advised. Oraling the photos.ephedrine has been successful in one patient with recurrent edema

(which was presumed to act via correction of hyperaldosteron-Referencesism).[52]

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Skin-Related Complications of Insulin Therapy